Navigating the Management of Chronic Phase CML in the Era of Generic BCR::ABL1 Tyrosine Kinase Inhibitors

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Ponatinib is a third‐generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with high potency against Philadelphia chromosome (Ph)‐positive leukemias, including T315I‐mutated disease, which is resistant to first‐ and second‐generation TKIs. Ponatinib was approved for T315I‐mutated chronic myeloid leukemia (CML), CML resistant/intolerant to ≥2 prior TKIs, advanced phase CML and Ph‐positive acute lymphoblastic leukemia (ALL) where no other TKIs are indicated, and T315I‐mutated CML and Ph‐positive ALL. The response‐based dosing of ponatinib in chronic phase CML (CP‐CML) improved treatment tolerance and reduced the risk of toxicities, including cardiovascular risks. Ponatinib‐based therapy also resulted in significantly better outcomes in frontline Ph‐positive ALL compared with prior TKIs and is becoming a new standard of care in this setting. As the clinical development of third‐generation TKIs and their rational combinations progresses, we envision further transformative changes in the treatment of CML and Ph‐positive ALL.

Ponatinib‐review of historical development, current status, and future research

Kantarjian,

Chifotides,

Haddad

et al. 2024

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Chronic myeloid leukemia: 2025 update on diagnosis, therapy, and monitoring

Jabbour,

Kantarjian

2024

Disease overviewChronic myeloid leukemia (CML) is a myeloproliferative neoplasm with an annual incidence of two cases/100 000. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults.DiagnosisCML is characterized by a balanced genetic translocation, t(9;22) (q34;q11.2), involving a fusion of the Abelson murine leukemia (ABL1) gene from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein.Frontline therapyFour tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib, are approved by the United States Food and Drug Administration (FDA) for first‐line treatment of newly diagnosed CML in the chronic phase (CML‐CP). Clinical trials with second and third‐generation TKIs in frontline CML‐CP therapy reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of their potent efficacy and the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. All four TKIs are equivalent if the aim of therapy is to improve survival. In younger patients with high‐risk disease and in whom the aim of therapy is to induce a treatment‐free remission status, second‐generation TKIs may be favored.Salvage therapyFor CML post‐failure on frontline therapy, second‐line options include second and third‐generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities and financial status, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib, asciminib, and olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML‐CP and failure (due to resistance) of at least two TKIs and for all patients in advanced‐phase disease. Older patients who have a cytogenetic relapse post‐failure on all TKIs can maintain long‐term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non‐TKI anti‐CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, and others).

Optimal frontline therapy of chronic myeloid leukemia today, and related musings

Kantarjian,

Begna,

Jabbour

et al. 2024